Much of the focus of new therapies for cancer has shifted in the last 5 years to include immunotherapy. This is in part due to the rapid, profound and durable responses seen with immune checkpoint inhibitors. However, these important clinical results are only seen in a subset of patients, ones with and underlying immune recognition of the tumor. Data from Dr. Gulley's clinical trials has suggested that therapeutic vaccines can efficiently generate immune recognition and activation against targets present in the vaccine and found in tumor cells (multiple publications). In addition, there is an increased infiltrate following vaccine (presented ASCO 2018). However, this anti-tumor immune response may not be sufficient to generate an improvement in clinical outcome for the patient without providing for adequate effector functionality within the tumor microenvironment. There are multiple immune checkpoints that are engaged on immune activation. CCR preclinical studies suggested synergy of vaccine with CTLA4 blockade. Dr. Gulley was the PI of one of the first studies combining a CCR developed vaccine (PSA-TRICOM) along with ipilimumab, an anti-CTLA4 antibody. Up to 10 mg/kg of ipilimumab was safely administered with PSA-TRICOM. Immune-related adverse events were similar in proportion and grade to those previously reported with ipilimumab alone. Furthermore, while the median predicted survival was about 18 months based on a validated nomogram, actual median OS exceeded 34 months in this phase I study. This also compares favorably to OS data of ipilimumab alone, however a randomized study would be required to validate these hypothesis generating findings. Recent clinical data on PD1 or PDL1 inhibition have accelerated interest in the field of immunotherapy. Dr. Gulley is the coordinating PI of a phase I dose-escalation study of the only anti-PDL1 antibody designed to not only antagonize PDL1, but to initiate antibody mediated cellular cytotoxicity (ADCC). This first-in-human international study of this agent sponsored by our CRADA partner, EMD-Serono, enrolled 125 patients at the NIH Clinical Center and has demonstrated dramatic prolonged responses seen in a variety of cancers including lung cancer, thymic epithelial malignancies, mesothelioma, bladder cancer and ovarian cancer. Our data also demonstrated no impact of ADCC on immune cells which can also express PDL1 (albeit often at lower levels than tumor cells). Based on this clinical data the FDA recently approved avelumab for use in patients with bladder cancer. This data was also used in part to approve avelumab for Merkel Cell Carcinoma. However, immune checkpoint inhibition requires an underlying anti-tumor immune response that it can unleash. In prostate cancer, the level of activated immune cells within the prostate is limited. Thus, combining vaccine with PDL1 blockade is a rational immunotherapeutic approach. We now have multiple ongoing studies in the CCR looking at vaccine with immune checkpoint inhibition. We also have recently opened a first-in-human, first-in-class anti-PDL1/TGF Beta Trap agent (M7824) with initial data presented at ASCO 2017 and ASCO 2018 demonstrating safety and preliminary evidence of activity (including PRs and a CR in the first 19 patients tested). The activity appears to be increased in HPV associated cancers (about 35% ORR) and in non-small cell lung cancer (about 28% ORR) compared to PD-1 or PDL-1 inhibition alone (data presented at ASCO 2018). This study has opened the door for multiple combination therapy studies utilizing M7824 to block two important negative regulatory mechanisms that dampen an effective anti-cancer immune response. These ongoing studies will also have built in biopsies and other correlative studies to analyze the impact of the combined therapy on the tumor microenvironment. In addition, the use of standard of care therapies to facilitate immune recognition and / or killing of the tumor, a process called immunogenic modulation, has been tested by Dr. Gulley. Data from 2 small, recently published CCR randomized phase II studies of standard therapy with or without vaccine suggest that this approach may impact progression free survival. Several vaccines have been developed within the CCR in association with BN, our CRADA partner. These include Prostvac (PSA-TRICOM), which contains genes for prostate-specific antigen (PSA) and a triad of costimulatory molecules (TRICOM), and Panvac, which contains CEA, MUC-1 and TRICOM. One combination trial in prostate cancer suggest an improvement in PFS: Quadramet with or without Prostvac vaccine (1.7 vs. 3.7 months, P = 0.041, HR 0.51) in 44 patients with disease metastatic to bone (Oncotarget 2016). A breast cancer trial comparing docetaxel with or without Panvac vaccine in 48 patients with metastatic disease shows a trend that met protocol specified criteria favoring the combination in PFS (7.9 vs. 3.9 months, P = 0.09, HR 0.65) meeting the pre-defined criteria for a positive study (JAMA Oncology 2015). The ability to use PFS as a discriminatory endpoint for combination studies has the potential to significantly expedite analysis in proof-of-concept efficacy studies in immunotherapy (phase II) and may also improve patient outcomes over standard therapy alone. An ongoing collaborative study (GMB, UOB, LTIB) is evaluating BCG with or without Panvac in patients with superficial bladder cancer who have recurrence despite prior BCG.